Role of Membranes in the Pore-formation Mechanism of Pore-forming Proteins and Toxins

Selective permeability barrier function of the plasma membrane is essential in maintaining the compartmentalized cellular architecture. Any damage to the plasma membrane can be detrimental to the cellular homeostasis, and can eventually lead to cell death.

Pore-forming proteins/toxins (PFPs/PFTs) constitute a unique class of membrane-damaging proteins. They show the remarkable ability to form oligomeric pores in the membrane lipid bilayer. Ability of the PFPs/PFTs to punch holes in the cell membranes designates them as the Nature’s one of the most efficient cell-killing entities. PFPs/PFTs are documented in the diverse life forms starting from pathogenic microorganisms to human. Two of the most important examples of the PFPs, implicated for the execution of the immune responses in humans, include the membrane-attack complex (MAC) of the complement pathway, and perforin protein, produced by the cytotoxic T lymphocytes. Pathogenic bacteria employ PFTs for the execution of their virulence mechanisms. Notably, more than one-third of the bacterial protein toxins belong to the PFT family.

PFPs/PFTs are often appreciated as a remarkable group of dimorphic proteins. They are generally produced/secreted as soluble monomeric molecules, and upon encountering the target cell membranes, they convert into membrane-embedded oligomeric pore complexes. Metamorphosis of the PFPs/PFTs from their soluble precursor form into the oligomeric membrane-damaging pore state involves large-scale structural/conformation/assembly changes within the proteins’ molecular architecture. It is well-appreciated that the membrane lipid bilayer plays a pivotal role in orchestrating the pore-formation mechanism of the PFPs/PFTs. In most of the cases, pore-formation process can be executed by the PFPs/PFTs in the lipid bilayer, without any essential requirement of the non-lipid components of the membrane. Thus, membrane lipid bilayer appears to act almost like a catalytic platform to support the pore formation process of the PFPs/PFTs. It is well-established that specific membrane lipid components play crucial roles in regulating pore-formation mechanism of many PFPs/PFTs. Even in certain cases, specific membrane lipids serve a receptor-like role. It is now also being appreciated that the specific physicochemical features of the membrane environment (such as, the distribution of the ordered/disordered phases of the membrane microdomains) can also influence the efficacy of membrane pore formation. Despite all these insights, it still remains intriguing how the membrane environment triggers the intricate cascade of structural/assembly changes in the PFPs/PFTs.

This special issue will showcase review articles, perspectives, and original research articles on the roles of membranes in regulating the pore-formation mechanisms of PFPs/PFTs.